Synergy by Perturbing the Gram-Negative Outer Membrane: Opening the Door for Gram-Positive Specific Antibiotics

Abstract

New approaches to target antibacterial agents toward Gram-negative bacteria are key, given the rise of antibiotic resistance. Since the discovery of polymyxin B nonapeptide as a potent Gram-negative outer membrane (OM)-permeabilizing synergist in the early 1980s, a vast amount of literature on such synergists has been published. This Review addresses a range of peptide-based and small organic compounds that disrupt the OM to elicit a synergistic effect with antibiotics that are otherwise inactive toward Gram-negative bacteria, with synergy defined as a fractional inhibitory concentration index (FICI) of <0.5. Another requirement for the inclusion of the synergists here covered is their potentiation of a specific set of clinically used antibiotics: erythromycin, rifampicin, novobiocin, or vancomycin. In addition, we have focused on those synergists with reported activity against Gram-negative members of the ESKAPE family of pathogens namely, Escherichia coli , Pseudomonas aeruginosa , Klebsiella pneumoniae , and/or Acinetobacter baumannii . In cases where the FICI values were not directly reported in the primary literature but could be calculated from the published data, we have done so, allowing for more direct comparison of potency with other synergists. We also address the hemolytic activity of the various OM-disrupting synergists reported in the literature, an effect that is often downplayed but is of key importance in assessing the selectivity of such compounds for Gram-negative bacteria.

Polylactide—Meso-Substituted Arylporphyrin Composites: Structure, Properties and Antibacterial Activity

“…It contains a large number of macromolecules of different chemical types. Gram-negative bacteria are distinguished by such an essential component of their cell walls as the lipopolysaccharide layer [ 45 , 46 ]. Porphyrin molecules, due to their inherent hydrophobicity, tend to interact with lipid fragments, while four nitrogen atoms (of which two atoms are amine nitrogen and two other atoms are imine nitrogen) allow porphyrins to form hydrogen bonds with sugar residues.…”

Antibiotic Adjuvants: A Versatile Approach to Combat Antibiotic Resistance

“…195 Over the years, derivatives of polyamines have shown good potentiation ability. 172,196,197 For example, our efforts led to the development of D-LANA-14 (69) which is a synthetic cationic lipopeptide-based small molecule which shows good activity against Gram-positive bacteria but high MIC values against Gram-negative bacteria (Figure 9). 198 This compound was used at subinhibitory concentrations in combination with obsolete antibiotics, rifampicin and tetracycline, to combat Gram-negative superbugs.…”

“…Various antimicrobial peptides, cationic and cyclic lipopeptides, and antimicrobial peptide mimics have exhibited synergy with different classes of antibiotics. , Peptides derived from cathelicidins, lactoferrin, thrombin, histatins, other natural AMPs as well as rationally designed peptides have shown potentiation of antibiotics like vancomycin, erythromycin, azithromycin, rifampicin, novobiocin, fusidic acid, etc. against Gram-negative bacteria by perturbing their outer membrane owing to interaction with lipopolysaccharide present in the outer membrane .…”

A Dual Detergent Strategy to Capture a Bacterial Outer Membrane Proteome in Peptidiscs for Characterization by Mass Spectrometry and Binding Assays

“…The outer membrane of Gram-negative bacteria forms a formidable barrier that is the cell’s first line of defense against many antimicrobials, including antibiotics. This natural impermeability is conferred by a relatively rigid and asymmetric lipid bilayer, which contains phospholipids on the inner leaflet and glycolipidsknown as lipopolysaccharides (LPS)on the outer leaflet. − In addition to these lipid species, the outer membrane contains two major classes of proteins: (i) β-barrel proteins, which are integral to the lipid bilayer, and (ii) lipoproteins, which are covalently tethered to the membrane via a lipid moiety. ,,− In this study, these two protein classes are termed outer membrane proteins (OMPs) and collectively referred to as the “outer membrane proteome”. The importance of this outer membrane proteome and associated lipid components in restricting cell permeability is underscored by the observation that mutations affecting outer membrane integrity result in decreased bacterial virulence and increased susceptibility to antibiotics. − …”

“…This latter observation confirms that peptidisc-reconstituted OMPs are correctly folded and retain affinity for naturally occurring protein binders. This enrichment of the outer membrane proteome in peptidiscs may therefore be useful, not only for a systematic analysis of other bacterial outer membrane proteomes, but also for the discovery of next-generation antimicrobials, especially those of clinical concern due to their high resistance to current antibiotics, such as the ESKAPE pathogens A. baumannii , P. aeruginosa , K. pneumoniae , and Enterobacter . ,, …”